Ultra-High Molecular WeightPolyethylene: Influence of the Chemical,

Physical and Mechanical Propertieson the Wear Behavior. A Review

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Citation Bracco, Pierangiola, Anuj Bellare, Alessandro Bistolfi, and SaverioAffatato. 2017. “Ultra-High Molecular Weight Polyethylene: Influenceof the Chemical, Physical and Mechanical Properties on the WearBehavior. A Review.” Materials 10 (7): 791. doi:10.3390/ma10070791.http://dx.doi.org/10.3390/ma10070791.

Published Version doi:10.3390/ma10070791

Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:34375081

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materials

Review

Ultra-High Molecular Weight Polyethylene: Influenceof the Chemical, Physical and Mechanical Propertieson the Wear Behavior. A Review

Pierangiola Bracco 1,* ID , Anuj Bellare 2, Alessandro Bistolfi 3 and Saverio Affatato 4 ID

1 Department of Chemistry and NIS (Nanostructured Interfaces and Surfaces) Center, University of Torino,10125 Torino, Italy

2 Department of Orthopedic Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston,MA 02115, USA; anuj@alum.mit.edu

3 CTO Hospital, Città della salute e della Scienza, 10126 Torino, Italy; abistolfi@cittadellasalute.to.it4 Medical Technology Laboratory, Rizzoli Orthopaedic Institute, 40136 Bologna, Italy; affatato@tecno.ior.it* Correspondence: pierangiola.bracco@unito.it; Tel.: +39-011-670-7547

Received: 17 June 2017; Accepted: 8 July 2017; Published: 13 July 2017

Abstract: Ultra-high molecular weight polyethylene (UHMWPE) is the most common bearingmaterial in total joint arthroplasty due to its unique combination of superior mechanical propertiesand wear resistance over other polymers. A great deal of research in recent decades has focusedon further improving its performances, in order to provide durable implants in young and activepatients. From “historical”, gamma-air sterilized polyethylenes, to the so-called first and secondgeneration of highly crosslinked materials, a variety of different formulations have progressivelyappeared in the market. This paper reviews the structure–properties relationship of these materials,with a particular emphasis on the in vitro and in vivo wear performances, through an analysis of theexisting literature.

Keywords: UHMWPE; Ultra-high molecular weight polyethylene; oxidation; degradation; gammaradiation; crosslinking; Vitamin E; mechanical properties; wear

1. Introduction

Ultra-high molecular weight polyethylene (UHMWPE) has been used as a bearing material intotal joint arthroplasty for more than 50 years now. The idea to replace degraded cartilage with apolymer liner dates back to the late 1950s. At that time, Sir John Charnley chose polytetrafluoroethylene(PTFE), a low friction polymer, as the bearing material to replace the natural acetabulum, articulatingagainst a metallic femoral head, for hip replacement. Due to the unacceptably low wear resistance ofPTFE though, the first “low friction arthroplasties” dramatically failed after few years of implantation.In 1962, UHMWPE, a similarly low-friction, but much more wear resistant polymer, replaced PTFE inCharnley’s hip arthroplasty, with remarkably better performances. From then on, arthroplasty hasknown considerable evolution, but UHMWPE remains the gold standard for artificial hips and nowother artificial joints, including the knee and shoulder [1].

Despite a relatively successful history, the steadily increasing number of yearly procedures [2,3]and, above all, the dramatic increase of demand in younger, more active patients [4] have stimulateda constant research for optimized material formulations and processing procedures, to ensure a highlevel of performance and durability.

Each potential innovation has been accompanied by a great deal of pre-clinical trials, performedby researchers all over the world, often with very different methods and sometimes withcontradictory results.

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Only some of these studies were aimed at establishing a correlation between the chemical andmorphological characteristics of the polymer and its mechanical properties and wear resistance.In some cases, retrieval studies have correlated the material properties to the clinical outcome ofthe implant.

The present work aims at exploring such a correlation through an analysis of the relevant literaturethat has appeared in the last decades.

2. UHMWPE

UHMWPE is a particular type of polyethylene (PE), with an exceptionally high molecular mass.The international Standards Organization (ISO 11542) (ISO, 2001) defines UHMWPE as havinga molecular weight of at least 1 million g/mol, while the American Society for Testing and Materials(ASTM) specifies that UHMWPE has a molecular weight greater than 3.1 million g/mol [5]. Besidesthe molecular mass, the microstructure of the polymer also plays an important role in determining itsphysical, chemical and mechanical properties. UHMWPE, as most polyethylenes, is a semi-crystallinepolymer composed of at least two interpenetrating phases: a crystalline phase, in which themacromolecules fold into ordered, crystalline lamellae and an amorphous, disordered phase, possiblyintercalated by a partially ordered, so called all-trans, interphase [6,7].

The UHMWPE used in orthopaedic applications typically has a molecular weight between3.5–6 million [8] and semi-finished bars and rods have a degree of crystallinity ranging around50–55%. Such a precise combination of chemical structure, molecular mass and microstructure is atthe basis of the peculiar balance of high mechanical properties and wear resistance that has madeUHMWPE the material of choice in arthroplasty. A high entanglement density is associated withthe ultra-high molecular weight; entanglements behave like physical crosslinks, which affect itscrystalline morphology when the polymer is melt-crystallized. Unlike its lower molecular weightcounterparts, UHMWPE crystallizes into a non-spherulitic structure comprising tortuous, defectivelamellae. The high entanglement density is responsible for the relatively low crystallinity, comparedto medium and low molecular weight, linear, high density polyethylene (HDPE) which can be meltcrystallized to a degree of crystallinity of 70–80%. It is generally believed that the higher toughnessand wear resistance of UHMWPE is associated with a large number of inter-lamellar tie moleculesconnecting adjacent lamellae, compared to HDPE. Furthermore, inter-spherulitic boundaries of HDPEare known to be weak since melt crystallization “sweeps” any impurities present in the melt tospherulitic boundaries which are also thought to contain a larger concentration of chain ends than theamorphous layers between lamellae. The suppression of spherulite formation in UHMWPE then mustalso contribute to the overall toughness and high wear resistance of UHMWPE. UHMWPE resin hasan essentially zero melt flow index. As a result, upon melting of UHMWPE resin particles, that areusually approximately 50–150 µm in diameter, do not flow and instead retain their shape. This makesit extremely difficult to injection mold the powder to directly constitute implants and instead, the resinis compression molded or ram extruded into bars at elevated pressure and temperature, and thenannealed to remove residual stresses. It is then machined into implants, packaged and sterilized priorto implantation.

It is quite clear that any processing step must be carefully controlled, from consolidation of thepowder at elevated temperatures and pressures, to radiation sterilization, to addition of antioxidants oranti-slip agents or to any other specific treatment that can potentially influence such a balance and thuslead to changes in macroscopic mechanical and tribological properties As with any semicrystallinepolymer, the microstructure and nanoscale lamellar morphology of UHMWPE depends on its thermalhistory during molding or ram extrusion. Unlike PEs with lower molecular weight, the consolidationof UHMWPE resin particles is a slow process due to the large time scales associated with reptationof chains of high molecular weight across resin boundaries to entangle with chains in adjacentresin particles and co-crystallize to form a fused article, assisted by pressure and temperature.Chain reptation, derived from the word “reptile”, is the thermal motion of entangled macromolecules

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in a tube, much like the slithering of snakes. In fact, it has been demonstrated that the extended-chainmorphology of the UHMWPE resin upon melting leads to “chain-explosion” which is the dominanttransport mechanism that leads to cocrystallization of chains across resin boundaries to fuse the resin,compared to the much slower chain reptation process [9]. The difficulty in fusion of resin particlesmakes the inter-powder boundaries weaker than the interior of resin particles, but overall providesa tough, highly wear resistant material with a relatively successful history of implantation as jointreplacement devices.

3. “Historical” and Conventional Radiation Sterilized Polyethylenes

The term “historical” often identified polyethylenes that were sterilized by 25–40 kGy of gammaradiation in air [10]. These types of polyethylene have a long clinical history, starting from the firstpioneering implants in the 1960s, up to the end of the 1990s, by which time most manufacturershad switched to inert-sterilized, barrier packaging PE and/or to crossliked PE. However, examplesof gamma air sterilized polyethylenes can also sporadically be found in contemporary clinicalapplications [10,11].

A body of literature, in particular across the late 1980s to the early 2000s, investigated the effectsof radiation sterilization in air on the chemical, physical, mechanical and tribological properties ofpolyethylene [12–18]. Basically, high energy irradiation leads to the cleavage of chemical bonds of thePE chains, creating free radicals. The free radicals are highly reactive species that tend to producea complex series of reactions, the extent of which is strongly dependent on the surrounding speciesavailable for reaction [19]. In inert atmosphere, the predominating effect of irradiation is the formationof crosslinks among the polymer chains. Conversely, in an air environment, the radicals can easilyreact with oxygen, triggering a cyclic, auto-sustained process that results in the formation of oxidationproducts on the backbone of the polymer and, more importantly, in predominating chain scissions,with a consequent overall decrease in its molecular mass, and significant changes to its morphology(Figure 1). In particular, it has been demonstrated that, immediately after irradiation in air, crosslinkingand an increase in crystallinity are the dominant processes. With time, chain scission induced byoxidation prevails, resulting in a further increase in crystallinity [20–22], likely through the formationof a new phase of thinner crystallites in the amorphous region [13].

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compared to the much slower chain reptation process [9]. The difficulty in fusion of resin particles makes the inter-powder boundaries weaker than the interior of resin particles, but overall provides a tough, highly wear resistant material with a relatively successful history of implantation as joint replacement devices.

3. “Historical” and Conventional Radiation Sterilized Polyethylenes

The term “historical” often identified polyethylenes that were sterilized by 25–40 kGy of gamma radiation in air [10]. These types of polyethylene have a long clinical history, starting from the first pioneering implants in the 1960s, up to the end of the 1990s, by which time most manufacturers had switched to inert-sterilized, barrier packaging PE and/or to crossliked PE. However, examples of gamma air sterilized polyethylenes can also sporadically be found in contemporary clinical applications [10,11].

A body of literature, in particular across the late 1980s to the early 2000s, investigated the effects of radiation sterilization in air on the chemical, physical, mechanical and tribological properties of polyethylene [12–18]. Basically, high energy irradiation leads to the cleavage of chemical bonds of the PE chains, creating free radicals. The free radicals are highly reactive species that tend to produce a complex series of reactions, the extent of which is strongly dependent on the surrounding species available for reaction [19]. In inert atmosphere, the predominating effect of irradiation is the formation of crosslinks among the polymer chains. Conversely, in an air environment, the radicals can easily react with oxygen, triggering a cyclic, auto-sustained process that results in the formation of oxidation products on the backbone of the polymer and, more importantly, in predominating chain scissions, with a consequent overall decrease in its molecular mass, and significant changes to its morphology (Figure 1). In particular, it has been demonstrated that, immediately after irradiation in air, crosslinking and an increase in crystallinity are the dominant processes. With time, chain scission induced by oxidation prevails, resulting in a further increase in crystallinity [20–22], likely through the formation of a new phase of thinner crystallites in the amorphous region [13].

Figure 1. Cross-section of a gamma-air sterilized tibial insert, exhibiting a characteristic “crown-effect” (subsurface white band), along with its Fourier Transform InfraRed (FTIR) spectra, showing the presence of abundant oxidation products. Adapted from [17], with permission.

The extent and rate of radiation-induced oxidation depends on several factors, including the total absorbed dose and dose rate, the temperature of the sterilization facility, the oxygen availability and the sample thickness, which in turn governs the oxygen concentration distribution through the

Figure 1. Cross-section of a gamma-air sterilized tibial insert, exhibiting a characteristic “crown-effect”(subsurface white band), along with its Fourier Transform InfraRed (FTIR) spectra, showing thepresence of abundant oxidation products. Adapted from [17], with permission.

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The extent and rate of radiation-induced oxidation depends on several factors, including thetotal absorbed dose and dose rate, the temperature of the sterilization facility, the oxygen availabilityand the sample thickness, which in turn governs the oxygen concentration distribution through thethickness of the implant. In addition, the oxidative process initiated during sterilization can continue,with variable yet low rates, during shelf storage and implantation (post-irradiation aging). Again,the rate and extent of oxidative degradation depend on the shelf-aging time and temperature andon the amount of available oxygen in the shelf and in vivo [19]. Further, it appears that mechanicalstresses developed during in vivo use can also facilitate the oxidative process [23,24]. In summary,it follows that sterilization by high energy radiation in the presence of air can result in highly variableoxidation levels in polyethylenes, influenced by multiple factors.

Overall, oxidative degradation has been demonstrated to lead to significant changes in themechanical properties of UHMWPE and, in particular, to embrittlement. Brittleness of polymers is wellknown to be correlated to the tensile properties [25,26]. Accordingly, an increase in elastic modulusand a decrease in the elongation to failure, ultimate stress and toughness has been demonstrated bya number of studies [27–29] (Figure 2); moreover, a decrease in fatigue crack propagation resistancehas also been observed [20,30], while an often dramatic decrease in wear resistance (Figure 3) has beendemonstrated by multiple in vitro and retrieval studies [22,29,31–34].

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thickness of the implant. In addition, the oxidative process initiated during sterilization can continue, with variable yet low rates, during shelf storage and implantation (post-irradiation aging). Again, the rate and extent of oxidative degradation depend on the shelf-aging time and temperature and on the amount of available oxygen in the shelf and in vivo [19]. Further, it appears that mechanical stresses developed during in vivo use can also facilitate the oxidative process [23,24]. In summary, it follows that sterilization by high energy radiation in the presence of air can result in highly variable oxidation levels in polyethylenes, influenced by multiple factors.

Overall, oxidative degradation has been demonstrated to lead to significant changes in the mechanical properties of UHMWPE and, in particular, to embrittlement. Brittleness of polymers is well known to be correlated to the tensile properties [25,26]. Accordingly, an increase in elastic modulus and a decrease in the elongation to failure, ultimate stress and toughness has been demonstrated by a number of studies [27–29] (Figure 2); moreover, a decrease in fatigue crack propagation resistance has also been observed [20,30], while an often dramatic decrease in wear resistance (Figure 3) has been demonstrated by multiple in vitro and retrieval studies [22,29,31–34].

Figure 2. Small punch load displacement curves for gamma-air sterilized ultra-high molecular weight polyethylene (UHMWPE) tibial inserts at surface and subsurface locations: (a) control, unaged; (b) shelf-aged for 5 years; (c) shelf aged for 10 years. Adapted from [27], with permission.

Wear in this material has typically been measured as weight loss per million cycles after accounting for absorption of bovine serum during articulation against a metal or ceramic counterface. A control specimen is typically loaded and soaked in bovine serum but not articulated and fluid absorption is measured periodically along with worn specimens. Wear rate has also been reported as wear factor, which is the weight loss normalized by load and the total wear path traveled [35,36].

It is worth mentioning though, that several in vitro studies reported markedly better wear performances of gamma-air irradiated polyethylenes vs. unirradiated ones. For example, Essner and coworkers [37], in a comprehensive study investigating the clinical relevance of hip simulator experiments, demonstrated that the wear volume of non-sterilized and EtO sterilized cups was twice that of gamma-irradiated in air cups. Similarly, Affatato et al. [38] showed that after 5M cycles in a hip simulator, EtO-sterilized specimens wore 1.2 times faster than those gamma-irradiated and the

Figure 2. Small punch load displacement curves for gamma-air sterilized ultra-high molecular weightpolyethylene (UHMWPE) tibial inserts at surface and subsurface locations: (a) control, unaged;(b) shelf-aged for 5 years; (c) shelf aged for 10 years. Adapted from [27], with permission.

Wear in this material has typically been measured as weight loss per million cycles after accountingfor absorption of bovine serum during articulation against a metal or ceramic counterface. A controlspecimen is typically loaded and soaked in bovine serum but not articulated and fluid absorption ismeasured periodically along with worn specimens. Wear rate has also been reported as wear factor,which is the weight loss normalized by load and the total wear path traveled [35,36].

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It is worth mentioning though, that several in vitro studies reported markedly better wearperformances of gamma-air irradiated polyethylenes vs. unirradiated ones. For example, Essnerand coworkers [37], in a comprehensive study investigating the clinical relevance of hip simulatorexperiments, demonstrated that the wear volume of non-sterilized and EtO sterilized cups was twicethat of gamma-irradiated in air cups. Similarly, Affatato et al. [38] showed that after 5M cyclesin a hip simulator, EtO-sterilized specimens wore 1.2 times faster than those gamma-irradiatedand the same result was confirmed even in a subsequent test in a regime of third-body wear [39].McKellop et al. [40], in another hip simulator experiment, also found indistinguishable wear ratesfor two cups, both gamma-irradiated in air, made of different resins (GUR 4150 and 1020, with andwithout calcium stearate), and a 54% higher wear rate for a cup made with the same GUR 4150 resin,sterilized with ethylene oxide.

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same result was confirmed even in a subsequent test in a regime of third-body wear [39]. McKellop et al. [40], in another hip simulator experiment, also found indistinguishable wear rates for two cups, both gamma-irradiated in air, made of different resins (GUR 4150 and 1020, with and without calcium stearate), and a 54% higher wear rate for a cup made with the same GUR 4150 resin, sterilized with ethylene oxide.

Figure 3. Retrieved polyethylene tibial insert showing severe wear damage, including severe delamination and wear (10 years in vivo).

This likely occurs because, as highlighted above, gamma irradiation results in a combination of crosslinking and chain scission, the latter prevailing only after an extended time of post irradiation aging. Given the opposite effect of these two phenomena on the wear resistance of UHMWPE [17,33,41,42], it becomes apparent that radiation sterilized samples will exhibit less wear of unirradiated or EtO/gas plasma sterilized ones, at a short post irradiation time scale and storage conditions that allow crosslinking to prevail to a larger extent than chain scission. On the contrary, after suitable accelerated ageing or longer real time aging, in the shelf or in vivo, the wear and fatigue performances of gamma irradiated samples deteriorate considerably as a consequence of oxidative degradation and negate any short term benefits of crosslinking associated with sterilization methods that use ionizing radiation [21,29,32,33,43].

This observation prompted researchers in the field to implement strategies to take advantage of the benefit of the crosslinking induced by radiation treatments, yet minimizing the drawback of long-term oxidation.

The first adopted measure was to sterilize UHMWPE with high energy radiation in a low-oxygen environment (vacuum or inert gas, i.e., argon or nitrogen) [10,44–46]. This practice avoids contact with oxygen during sterilization and, if the liner is wrapped in a suitable barrier packaging, during the following shelf life as well [11,47]. Unfortunately, it does not prevent contact with the oxygen solubilized into polyethylene before packaging in the low-oxygen environment, nor with that available in vivo [43], so that some oxidation has also been observed in these polyethylenes, even if to much lower levels than for those radiation sterilized in air [11,48,49].

4. 1st Generation Highly Crosslinked Polyethylene

4.1. Improving the Wear Resistance

By the late 1990s, a large number of laboratory and clinical studies indicated that crosslinking provides substantial improvement in the wear resistance of UHMWPE. The mechanisms by which this improvement occurs were elucidated by various researchers [41,42,50–52]. Basically, wear of UHMWPE is believed to take place via plastic deformation of the polymer, with molecular alignment in the direction of motion that results in the formation of fine, drawn-out fibrils oriented parallel to each other. As a result of this arrangement, the UHMWPE wear surface may strengthen along the direction of sliding, while it weakens in the transverse direction. Wang et al. [50] concluded that,

Figure 3. Retrieved polyethylene tibial insert showing severe wear damage, including severedelamination and wear (10 years in vivo).

This likely occurs because, as highlighted above, gamma irradiation results in a combinationof crosslinking and chain scission, the latter prevailing only after an extended time of postirradiation aging. Given the opposite effect of these two phenomena on the wear resistance ofUHMWPE [17,33,41,42], it becomes apparent that radiation sterilized samples will exhibit less wearof unirradiated or EtO/gas plasma sterilized ones, at a short post irradiation time scale and storageconditions that allow crosslinking to prevail to a larger extent than chain scission. On the contrary,after suitable accelerated ageing or longer real time aging, in the shelf or in vivo, the wear and fatigueperformances of gamma irradiated samples deteriorate considerably as a consequence of oxidativedegradation and negate any short term benefits of crosslinking associated with sterilization methodsthat use ionizing radiation [21,29,32,33,43].

This observation prompted researchers in the field to implement strategies to take advantageof the benefit of the crosslinking induced by radiation treatments, yet minimizing the drawback oflong-term oxidation.

The first adopted measure was to sterilize UHMWPE with high energy radiation in a low-oxygenenvironment (vacuum or inert gas, i.e., argon or nitrogen) [10,44–46]. This practice avoids contactwith oxygen during sterilization and, if the liner is wrapped in a suitable barrier packaging, duringthe following shelf life as well [11,47]. Unfortunately, it does not prevent contact with the oxygensolubilized into polyethylene before packaging in the low-oxygen environment, nor with that availablein vivo [43], so that some oxidation has also been observed in these polyethylenes, even if to muchlower levels than for those radiation sterilized in air [11,48,49].

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4. 1st Generation Highly Crosslinked Polyethylene

4.1. Improving the Wear Resistance

By the late 1990s, a large number of laboratory and clinical studies indicated that crosslinkingprovides substantial improvement in the wear resistance of UHMWPE. The mechanisms by whichthis improvement occurs were elucidated by various researchers [41,42,50–52]. Basically, wear ofUHMWPE is believed to take place via plastic deformation of the polymer, with molecular alignmentin the direction of motion that results in the formation of fine, drawn-out fibrils oriented parallel toeach other. As a result of this arrangement, the UHMWPE wear surface may strengthen along thedirection of sliding, while it weakens in the transverse direction. Wang et al. [50] concluded that,under the conditions of multi-directional motion, which may apply to both the hip and the knee joint,this orientation-softening phenomenon is predominantly responsible for the detachment of fibrouswear debris from the worn surfaces that have been observed in many reports [53–55]. Therefore, it hasbeen postulated that, since crosslinking induces carbon-carbon bonds between adjacent chains, herebyreducing the chain mobility and inhibiting such molecular orientation, it would have been efficientin slowing down the formation of surface fibrils and rendering the polyethylene more resistant towear [41,51,56].

Although some controversies do exist in the literature, regarding the chemical mechanismsof radiation crosslinking of UHMWPE [19,56–58], most authors agree that the crosslinking densityincreases linearly up to radiation doses in the order of 100 kGy, above which it tends to a plateau(Figure 4a) [42]. However, the decrease in the tensile and fracture toughness continues at a radiationdose higher than 100 kGy [59,60]. Therefore, most of the “1st generation” highly crosslinkedpolyethylenes appeared in experimental in vitro and clinical studies at the end of the 1990s andin the early 2000s were irradiated to doses between 50 and 105 kGy [5].

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under the conditions of multi-directional motion, which may apply to both the hip and the knee joint, this orientation-softening phenomenon is predominantly responsible for the detachment of fibrous wear debris from the worn surfaces that have been observed in many reports [53–55]. Therefore, it has been postulated that, since crosslinking induces carbon-carbon bonds between adjacent chains, hereby reducing the chain mobility and inhibiting such molecular orientation, it would have been efficient in slowing down the formation of surface fibrils and rendering the polyethylene more resistant to wear [41,51,56].

Although some controversies do exist in the literature, regarding the chemical mechanisms of radiation crosslinking of UHMWPE [19,56–58], most authors agree that the crosslinking density increases linearly up to radiation doses in the order of 100 kGy, above which it tends to a plateau (Figure 4a) [42]. However, the decrease in the tensile and fracture toughness continues at a radiation dose higher than 100 kGy [59,60]. Therefore, most of the “1st generation” highly crosslinked polyethylenes appeared in experimental in vitro and clinical studies at the end of the 1990s and in the early 2000s were irradiated to doses between 50 and 105 kGy [5].

Figure 4. (a) Crosslink density and (b) pin-on-disk (POD) wear rate of irradiated UHMWPE as a function of increasing dose. Adapted from [42] with permission.

4.2. How to Prevent Oxidation

However, as mentioned in the previous paragraph, numerous studies had already demonstrated an unacceptably low stability to oxidation of irradiated polyethylene. As a consequence, stabilization strategies were developed in order to minimize post-irradiation oxidative ageing. Basically, two different strategies were adopted: one involved post-irradiation melting of the polyethylene (remelting) [41,56], while the other included a thermal treatment, as well, but at a temperature below complete melting of the crystallites (annealing) [61,62]. In both cases, the rationale for the protocol was to eliminate or reduce the residual radicals, trapped in the crystalline phase of the polymer, as to avoid the oxidation cascade.

4.3. Microstructure, Mechanical Properties and Wear

Irradiation of polyethylene results in a slight increase in crystallinity with increases in the radiation dose, along with a marked decrease in elongation to failure and impact strength, a moderate decrease in ultimate strength and a slight increase in yield strength [41,63]. Post-irradiation remelting causes a significant decrease in crystallinity, accompanied by a reduction in yield and ultimate strengths [61,63] This likely occurs because the kinetics of crystallization is affected by the formation of a network structure due to the presence of crosslinks, which reduce the chain mobility and makes it more difficult for PE macromolecules to reptate and enter into growing lamellae. As a consequence, recrystallization of a radiation crosslinked UHMWPE always results in decreases in crystallinity [56,64]. Such a decrease in crystallinity is also associated to a decrease in fatigue resistance (Table 1) [30,60,63,65–67]. On the contrary, post-irradiation annealing does not cause a reduction in crystallinity, thus preserving superior yield, ultimate and fatigue properties, with respect to remelting [61,65–67], at least in the short term.

Figure 4. (a) Crosslink density and (b) pin-on-disk (POD) wear rate of irradiated UHMWPE asa function of increasing dose. Adapted from [42] with permission.

4.2. How to Prevent Oxidation

However, as mentioned in the previous paragraph, numerous studies had already demonstratedan unacceptably low stability to oxidation of irradiated polyethylene. As a consequence, stabilizationstrategies were developed in order to minimize post-irradiation oxidative ageing. Basically,two different strategies were adopted: one involved post-irradiation melting of the polyethylene(remelting) [41,56], while the other included a thermal treatment, as well, but at a temperature belowcomplete melting of the crystallites (annealing) [61,62]. In both cases, the rationale for the protocol wasto eliminate or reduce the residual radicals, trapped in the crystalline phase of the polymer, as to avoidthe oxidation cascade.

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4.3. Microstructure, Mechanical Properties and Wear

Irradiation of polyethylene results in a slight increase in crystallinity with increases in the radiationdose, along with a marked decrease in elongation to failure and impact strength, a moderate decreasein ultimate strength and a slight increase in yield strength [41,63]. Post-irradiation remelting causesa significant decrease in crystallinity, accompanied by a reduction in yield and ultimate strengths [61,63]This likely occurs because the kinetics of crystallization is affected by the formation of a networkstructure due to the presence of crosslinks, which reduce the chain mobility and makes it more difficultfor PE macromolecules to reptate and enter into growing lamellae. As a consequence, recrystallizationof a radiation crosslinked UHMWPE always results in decreases in crystallinity [56,64]. Such a decreasein crystallinity is also associated to a decrease in fatigue resistance (Table 1) [30,60,63,65–67]. On thecontrary, post-irradiation annealing does not cause a reduction in crystallinity, thus preserving superioryield, ultimate and fatigue properties, with respect to remelting [61,65–67], at least in the short term.

Table 1. Physical properties and fatigue crack propagation data for a set of standard andcrosslinked/remelted UHMWPE (GUR 1050), at increasing gamma radiation doses. All crosslinkedsamples were remelted at 170 ◦C for 4 h and subsequently annealed at 125 ◦C for 2 days. Adaptedfrom [60] with permission.

Control 50 kGy 100 kGy 200 kGy

Crystallinity (%) 50.1 ± 0.5 45.6 ± 0.7 46.3 ± 0.8 47.1 ± 0.4Lamellar thickness (nm) 20.0 18.1 18.7 19.1Elastic modulus (MPa) 495 ± 56 412 ± 50 386 ± 23 266 ± 30

Yield stress (MPa) 20.2 ± 1.0 19.9 ± 0.8 18.9 ± 0.7 20.2 ± 1.0True stress at break (MPa) 315.5 ± 31.6 237.6 ± 12.3 185.7 ± 7.5 126.0 ± 14.0

Decrease in true stress at break (%) - 24 41 60∆Kincep (MPa

√m) 1.41 0.91 0.69 0.55

Decrease in ∆Kincep (%) - 35 51 61

Both highly crosslinked formulations demonstrated superior wear resistance during in vitro tests,when compared to unirradiated or conventional gamma air/gamma inert sterilized polyethylenes.

For example, the wear rates measured using a bi-directional pin-on-disk (POD) on a setof polyethylenes, e-beam irradiated at room temperature in air to doses ranging from 25 to300 kGy and subsequently melted (150 ◦C for 2 h under vacuum), were found to decrease sharplywith increasing the radiation dose: from 9.6 ± 0.7 g/million cycles for the control, unirradiatedsample, to 1.6 ± 0.3 g/million cycles for the 100 kGy irradiated and remelted sample, approachingan undetectable wear rate for radiation doses of the order of 300 kGy (Figure 4b) [42].

Similarly, acetabular cups machined from a polyethylene gamma-irradiated in air at doses rangingfrom 33 to 1000 kGy, remelted and EtO sterilized, demonstrated an 87% wear reduction with increasein the radiation dose from 33 to 95 kGy, when tested for 5 million cycles in a hip simulator; again,the wear decreased to undetectable levels at a radiation dose higher than 200 kGy [41]. In the samework, by observing the trade-off between the reduction in tensile properties and the increase in wearresistance with increasing the radiation dose, the authors concluded that approximately 100 kGyrepresents the most appropriate dose to reduce the wear below the threshold for clinically significanteffects, simultaneously preserving sufficient tensile properties.

Kurtz et al. [61] summarized the wear test results of seven independent hip simulator studies,all using the same hip simulator design and comparable conditions, of a conventional, gamma inertsterilized polyethylene (30 kGy gamma radiation, in nitrogen: N2-Vac™ Stryker Howmedica Osteonics,Mahwah, NJ, USA) vs. a highly crosslinked and annealed UHMWPE (75 kGy gamma radiation,annealing at 130 ◦C, 30 kGy gamma radiation in nitrogen for sterilization purpose, Crossfire™, StrykerHowmedica Osteonics, Mahwah, NJ, USA). Counterfaces included CoCr, alumina, and Zirconiaceramic femoral heads with sizes ranging between 28 and 36 mm. The linear wear rate was calculatedin the first 2 to 3 million cycles of the test to facilitate comparison between studies. Despite a relatively

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broad distribution in wear rates, which may be partly explained by variations in liner design, femoralhead material, and femoral head size, the survey demonstrated a 92% reduction in median wearrate for the highly crosslinked and annealed UHMWPE, relative to the conventional, gamma inertsterilized polyethylene.

4.4. Does the Counterface Matter with Crosslinked Polyethylene?

The influence of the type of counterface on the wear behavior of crosslinked polyethylene wasalso investigated. Bistolfi and coworkers [64] showed that a moderate dose (50 kGy) of radiationcrosslinking increased the wear resistance of UHMWPE against a CoCr counterface in a POD apparatus7-fold, but the coupling of remelted, crosslinked UHMWPE against a smoother alumina counterfaceled to a 20-fold increase in wear resistance. Affatato et al. [68] tested e-beam highly crosslinkedand remelted hip liners (95 kGy at 40 ◦C, thermally treated at 150 ◦C for 6 h, Gas Plasma sterilized.Longevity™, Zimmer Inc., Warsaw, IN, USA) in a hip simulator for 3 M cycles, against deliberatelyscratched femoral heads (mean surface roughness, Ra: 0.12–0.14 µm). Even in such demandingconditions, they reported a 40 times lower wear rate for the crosslinked material than for conventional,gamma-nitrogen sterilized UHMWPE.

A previous study [36] also demonstrated that moderately crosslinked UHMWPE (40 kGy invacuum, no thermal treatment) exhibited a 30% reduction in wear rate compared to unirradiatedpolyethylene, when articulating on smooth CoCr femoral heads. However, upon intentionallyscratched CoCr femoral heads the wear rate was found to be higher for the moderately crosslinkedpolyethylene than for the non-crosslinked materials. Most importantly, the moderately crosslinkedpolyethylene generated a higher percentage volume of smaller, more biologically active particles, thusresulting in a similar index of functional biological activity. The authors concluded that this evidenceprovides a clear message that is preferable to use crosslinked materials against damage-resistantceramic heads, to prevent the possibility of wear acceleration owing to third body damage to metallicfemoral heads. Another study by the same group [69] demonstrated a fivefold lower wear for 75and 100 kGy gamma irradiated and remelted polyethylenes, compared to control unirradiated or25 kGy irradiated in air, when tested for 5 M cycles in a hip simulator, against CoCr femoral heads.The wear reduction was found to be significantly higher for the material irradiated to 100 kGy. Inthis experiment, a large reduction in the functional biological activity of the wear particles generatedby the highly crosslinked material was also observed and it was attributed to the overall lower wearvolume found with this material. The same study also highlighted the influence of “bedding-in”,due to creep deformation, on the greater wear volume observed in the first million cycles for allpolyethylene configurations.

4.5. Thermal Treatments and Oxidation Stability

Regarding the oxidation stability of the two formulations of 1st generation highly crosslinkedpolyethylenes, McKellop and coworkers compared the oxidation stability and wear resistance of thesame set of samples mentioned above [41], with or without remelting, following accelerated ageing at80 ◦C in air for 20 to 30 days. The remelted cups exhibited little or no oxidation after artificial agingand no white bands, that are generally interpreted as a visual indication of oxidation [17], were presenton the cross sections of the remelted cups. In contrast, without remelting, there was considerableoxidation of the crosslinked cups, with subsurface oxidation peaks. White bands were present on thecross sections at the levels corresponding to maximum oxidation. Despite this oxidation, the wearrates of the cups, with or without remelting, were comparable before and after aging. However, it wasobserved that, being that the oxidized zones were located about 0.5 mm below the surface and giventhe low wear rates of the crosslinked cups, the wear did not penetrate into the oxidized layers of the notremelted cups, under the conditions of the experiment, but that, likely, this subsurface oxidation couldcause an increase in the wear rate after extended clinical use. This observation prompted the authors topostulate that remelting is an essential step to optimize the long-term performance of crosslinked cups.

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Muratoglu and coworkers [70] tested the oxidative stability of two highly crosslinkedpolyethylenes, one of which had been ebeam irradiated to 100 kGy, remelted (150 ◦C, 2 h) andterminally gas plasma sterilized, while the other had been gamma irradiated to 75 kGy, annealedbelow the melting temperature (120 ◦C) and gamma sterilized (25–35 kGy) in nitrogen. The PODwear rates of the two unaged samples were comparable and much lower than those of conventional,uncrosslinked samples. Residual free radicals were detected in the annealed samples by Electron SpinResonance (ESR), while they were not found in the remelted samples. Following accelerated ageing inair at 80 ◦C for 3 weeks, the annealed samples developed significant oxidation and their wear rate wasfound to increase by over an order of magnitude, while no oxidation or significant changes in the wearrate were observed for the remelted formulation.

In another study [71], the same annealed formulation was compared to a warm irradiated (95 kGyat 120 ◦C) and remelted PE. The two samples were real-time aged, in a pure, distilled water bathat 40 ◦C for 128 weeks. Again, at increasing aging times, the annealed sample showed increasingoxidation, with a maximum located at a subsurface level, while no oxidation was detected in theremelted PE (Figure 5). Upon testing the hip simulator wear rate of the real-time aged, annealedcomponents, the authors also observed that it was higher than the literature reported values of othercontemporary highly crosslinked UHMWPEs.

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components, the authors also observed that it was higher than the literature reported values of other contemporary highly crosslinked UHMWPEs.

Figure 5. Oxidation profiles of conventional UHMWPE (gamma-inert sterilized, 25–40 kGy), irradiated and once-annealed UHMWPE (CrossfireTM Stryker-Howmedica-Osteonics; Rutherford, NJ, USA), and irradiated and melted UHMWPE (DurasulTM Zimmer, formerly Centerpulse; Austin, TX, USA) after 128 weeks of real-time aqueous aging at 40 °C. Reproduced with permission from [71].

Collier et al. in an extensive study that compared the physical and mechanical properties of commercial, 1st generation crosslinked polyethylenes from six orthopaedic manufacturers [72], also concluded that, again, crosslinked/annealed PE was prone to oxidation, following accelerated aging, while all of the tested crosslinked/remelted materials showed oxidation resistance equal to that of never-irradiated polyethylene before and after accelerated aging and thus have the potential to remain relatively unaffected by oxidation throughout their duration in vivo.

Most of the aforementioned studies attributed the differences in the oxidative stability between remelted and annealed crosslinked polyethylenes to that a thermal treatment above the melting temperature (remelting), leads to a complete melting of the polymer crystallites, hereby allowing termination of the radicals trapped in the crystalline phase and thus brings the amount of residual radicals to undetectable levels [71,73]. Conversely, annealing just below the melting temperature leaves a measurable amount of free radicals in the polymer matrix, that can react with oxygen over time, thus triggering the oxidation cascade [61].

4.6. Clinical Outcomes and Retrieval Studies

Several clinical studies have reported superior in vivo wear performance of highly crosslinked PE, compared to conventional polyethylene in hip replacements [74–87], most of which were included in an extensive, systematic review of the clinical outcomes of 1st generation crosslinked polyethylene appearing at the beginning of the present decade [88]. Conversely, very few studies exist on the clinical performances of highly crosslinked polyethylene in the knee [89–91], partly because of a more limited introduction of this material in knee arthroplasty, due to recurrent concerns on its suitability, as a result of the loss in mechanical properties with increasing doses of radiation [88] and partly because of the lack of validated methods of determining the wear and damage rate of these components in vivo [56].

Figure 5. Oxidation profiles of conventional UHMWPE (gamma-inert sterilized, 25–40 kGy), irradiatedand once-annealed UHMWPE (CrossfireTM Stryker-Howmedica-Osteonics; Rutherford, NJ, USA), andirradiated and melted UHMWPE (DurasulTM Zimmer, formerly Centerpulse; Austin, TX, USA) after128 weeks of real-time aqueous aging at 40 ◦C. Reproduced with permission from [71].

Collier et al. in an extensive study that compared the physical and mechanical propertiesof commercial, 1st generation crosslinked polyethylenes from six orthopaedic manufacturers [72],also concluded that, again, crosslinked/annealed PE was prone to oxidation, following acceleratedaging, while all of the tested crosslinked/remelted materials showed oxidation resistance equal tothat of never-irradiated polyethylene before and after accelerated aging and thus have the potential toremain relatively unaffected by oxidation throughout their duration in vivo.

Most of the aforementioned studies attributed the differences in the oxidative stability betweenremelted and annealed crosslinked polyethylenes to that a thermal treatment above the meltingtemperature (remelting), leads to a complete melting of the polymer crystallites, hereby allowingtermination of the radicals trapped in the crystalline phase and thus brings the amount of residualradicals to undetectable levels [71,73]. Conversely, annealing just below the melting temperature

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leaves a measurable amount of free radicals in the polymer matrix, that can react with oxygen overtime, thus triggering the oxidation cascade [61].

4.6. Clinical Outcomes and Retrieval Studies

Several clinical studies have reported superior in vivo wear performance of highly crosslinkedPE, compared to conventional polyethylene in hip replacements [74–87], most of which were includedin an extensive, systematic review of the clinical outcomes of 1st generation crosslinked polyethyleneappearing at the beginning of the present decade [88]. Conversely, very few studies exist on the clinicalperformances of highly crosslinked polyethylene in the knee [89–91], partly because of a more limitedintroduction of this material in knee arthroplasty, due to recurrent concerns on its suitability, as a resultof the loss in mechanical properties with increasing doses of radiation [88] and partly because of thelack of validated methods of determining the wear and damage rate of these components in vivo [56].

A number of retrieval studies have also reported on the chemical, physical and mechanicalproperties of these highly crosslinked PE following in vivo aging. According to predictions of in vitrostudies, oxidation of the highly crosslinked/annealed formulation was reported by a number ofauthors [92–95]. Highly variable oxidation levels were measured in all the retrieval groups includedin these studies, although none of the components had been explanted specifically for polyethylenewear. All studies agreed that the highest oxidation is generally measured at the superior rim of thecomponent and not at the bearing surfaces and it was postulated that this occurs because of thegreater exposure of the rim area, compared to the bearing area, to molecular oxygen in the in vivoenvironment [96].

On the other hand, failures of some specific designs of highly crosslinked/remelted have also beendescribed in the literature [97,98]. Rim fractures have been observed in some components and havebeen attributed to the combination of reduced fatigue resistance induced by irradiation and remelting,with malpositioning and with particularly demanding designs, in terms of stress concentration [97].

As already mentioned, crosslinked/remelted polyethylenes did not contain free radicals at the timeof implantation and were expected to be stable to oxidation. Unexpectedly, some recent literature studiesreported that measurable levels of oxidation were observed in some retrievals [99–104]. Two concurrentcauses have been tentatively identified to explain such a surprising phenomenon. One is that thecyclic loading to which the components are exposed during in vivo service might have generated freeradicals, initiating mechano-oxidation [24,102]. The other involves the lipids absorbed in vivo from thesynovial fluid [105]. Oral et al. [106] demonstrated that, under accelerated aging conditions, squalene,a precursor in cholesterol synthesis, has the potential to accelerate oxidation in radical-free, irradiatedand melted UHMWPE.

Although the clinical significance of such adverse behaviors of the 1st generation highlycrosslinked PE is still under debate, their occurrence stimulated the research of alternative polyethyleneformulations to overcome the observed drawbacks.

5. 2nd Generation Highly Crosslinked Polyethylene

5.1. The Need for a 2nd Generation Crosslinked Polyethylene

The rationale at the basis of a new generation of highly crosslinked polyethylene was to maintainthe superior wear resistance demonstrated by the 1st generation crosslinked PE, while also retainingthe mechanical properties and fatigue resistance of the uncrosslinked material and ensuring stableproperties, thus oxidative stability, over time.

5.2. Sequentially Irradiated and Annealed Highly Crosslinked Polyethylene

As discussed in the previous paragraph, annealing below the melting temperature preserves mostof the original UHMWPE microstructure. Highly crosslinked/annealed PE had been demonstrated toretain mechanical properties and fatigue resistance similar to conventional, gamma-nitrogen sterilized

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(but unoxidized) material; however, the presence of free radicals in the latter leaves the polyethyleneexposed to oxidation [62]. Dumbleton and coworkers [107] proposed that it might have been possibleto create a highly crosslinked PE by using a sequential irradiation and annealing process. Sincea high (≥100 kGy) radiation dose creates many crosslinks that reduce the chain mobility, preventingan efficient elimination of the free radicals by annealing, they postulated that by using a low radiationdose (30 kGy), hereby spacing the crosslinks wider and providing higher chain mobility, annealingwould have been more efficient in eliminating free radicals. High crosslinking levels could stillbe obtained by sequentially repeating the irradiation and annealing steps so that the polyethylenecumulatively receives a high dose of radiation (approx. 90 kGy).

This 2nd generation crosslinked PE (X3™, Stryker Orthopaedics, Mahwah, NJ, USA) was terminallysterilized with gas plasma, so as to avoid the introduction of more free radicals with sterilization.Literature studies reported similar or only slightly reduced mechanical and fatigue properties comparedto conventional PE [62,67,107,108] and superior wear resistance in vitro [67,107–109] and in vivo [110,111].However, incomplete melting following irradiation leaves a low but measurable amount of free radicalsin the material [107,109], that was demonstrated to oxidize in vivo [100,103,112–114]. Although moststudies agreed that the measured levels of oxidation were generally low, in particular much lowerthan those reported for the 1st generation once-annealed highly crosslinked PE [100], and were notassociated with a decline in the clinical performance of the sequentially annealed PE [113], observationsof pitting and substantial material loss as well as subsurface white banding and cracking were alsoreported in a knee retrievals study [114]. More investigations and longer follow-up are thereforenecessary to assess the overall in vivo performance of this type of 2nd generation highly crosslinked PE.

5.3. Antioxidants: The New frontier

An alternative approach to the 2nd generation highly crosslinked polyethylene involves theaddition of an anti-oxidant stabilizer, in order to efficiently inhibit the oxidative degradation, withoutthe need for a thermal treatment of the irradiated polyethylene, so as to preserve the originalmorphology, mechanical properties and fatigue resistance [115]. Although this is a very commonapproach to stabilize polyolefins against oxidation [116], the addiction of additives to biomedicalUHMWPE had created concerns related to their biocompatibility for a long time. The first scientificpapers and patents mentioning the possibility of using vitamin E (α-tocopherol) as a biocompatiblestabilizer for UHMWPE [18,117] and exploring the subject are dated back to the late 1990s andonwards [118–120], but the first vitamin E-stabilized UHMWPE did not appear on the orthopedicmarket before 2007 [121,122]. Since then, though, a number of studies have investigated theperformances of crosslinked UHMWPE incorporating vitamin E [115,121–123], at the moment byfar the most used, and other stabilizers [124–128].

Two methods are currently used to incorporate vitamin E into UHMWPE [5,115]. One involvesblending of vitamin E with UHMWPE powder before consolidation and radiation crosslinking [121].The presence of vitamin E, a radical scavenger, in UHMWPE during irradiation protects thepolymer from oxidation [118,129–131] but reduces the efficiency of crosslinking [120,132]; therefore,the balance between the vitamin E concentration and the radiation dose must be optimized to obtaina simultaneously wear- and oxidation-resistant UHMWPE [133]. The alternative method is thediffusion of vitamin E into UHMWPE after radiation crosslinking [122]. The crosslinking efficiencyof UHMWPE is not adversely affected by this method, but a homogenization step is required afterincorporation to obtain adequate antioxidant concentration throughout the implants [134].

5.4. Mechanical Properties, Oxidation Stability and Wear Performances

Several studies have investigated the mechanical properties of both formulations of vitamin Estabilized PE. No significant differences in the static mechanical properties, nor in the fatigue crackpropagation resistance have been observed when comparing virgin UHMWPE with blends containingup to 5000 ppm of vitamin E [118,135]. Conversely, it has been demonstrated that highly crosslinked

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vitamin E-stabilized UHMWPE exhibits improved material properties compared to 1st generationhighly crosslinked PE. For example, vitamin E-doped 100-kGy irradiated UHMWPE demonstrateda 58% improvement in fatigue strength compared to irradiated and melted UHMWPE [136], attributedto the avoidance of the loss of crystallinity during post-irradiation melting. Moreover, the ultimatestrength, yield strength, elongation at break, and fatigue resistance of crosslinked vitamin E-stabilizedUHMWPE were significantly higher than that of 100 kGy–irradiated and melted UHMWPE [137].

In addition, Vitamin E-stabilized PE has demonstrated superior oxidation stability under a varietyof accelerated aging conditions. For example, blends of UHMWPE with 500, 1000 and 5000 ppm ofvitamin E, gamma irradiated to doses up to 100 kGy were found to be more oxidatively stable thanvirgin, unirradiated UHMWPE, following accelerated aging at 90 ◦C in air [129]. Oral et al. [136]showed that vitamin E-doped, irradiated UHMWPEs developed significantly lower oxidation levelscompared to 100-kGy irradiated UHMWPE after 5 weeks of accelerated aging at 80 ◦C in air, whileKurtz and coworkers [133] found that blending PE with doses of vitamin E as low as 125 ppmwas sufficient to avoid oxidation and maintain baseline mechanical and chemical properties, afterirradiation up to 75 kGy, through two weeks of accelerated aging, according to ASTM F 2003 (i.e., 70 ◦Cand 5 atm oxygen) (Figure 6).

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sufficient to avoid oxidation and maintain baseline mechanical and chemical properties, after irradiation up to 75 kGy, through two weeks of accelerated aging, according to ASTM F 2003 (i.e., 70 °C and 5 atm oxygen) (Figure 6).

Figure 6. (a) Small punch curves of virgin UHMWPE irradiated at 75 kGy in air: control and aged 2/4 weeks (ASTM F2003-00); (b) Small punch curves of UHMWPE blended with increasing concentrations (0–500 ppm) of vitamin E, irradiated at 75 kGy in air and aged 4 weeks; (c) Oxidation indexes of UHMWPE blended with increasing concentrations of vitamin E (0–500 ppm), irradiated at 75 kGy in air and aged 2/4 weeks. Adapted from [133], with permission.

The wear resistance of this 2nd generation highly crosslinked formulation has been extensively tested in several in vitro experiments, under a variety of challenging conditions, and has been compared to conventional and 1st generation highly crosslinked formulations before and after both accelerated and shelf-aging.

In a POD wear test, highly crosslinked Vitamin E-doped PE exhibited comparable wear rates to 1st generation highly crosslinked PE irradiated to the same dose [136], while it demonstrated a 4-fold to 10-fold decrease, respectively, from that of conventional UHMWPE in a hip simulator experiment with and without the addition of third-body particles [137].

Bellare et al. [138] compared the wear rates of vitamin E blended (1000 and 5000 ppm) vs. virgin UHMWPE, gamma irradiated to 30 and 100 kGy, before and after shelf aging for two years. The samples were also characterized for physical properties and crosslinking density: it was found that the crosslinking density increases with the radiation dose, but decreases with the vitamin E content. This was not surprising, as it is known that vitamin E, as a radical scavenger, can inhibit the crosslinking reactions [19]. Accordingly, the wear rates of the vitamin E containing samples were comparatively higher than that of virgin PE irradiated to the same dose, but lower than that of

Figure 6. (a) Small punch curves of virgin UHMWPE irradiated at 75 kGy in air: control and aged 2/4weeks (ASTM F2003-00); (b) Small punch curves of UHMWPE blended with increasing concentrations(0–500 ppm) of vitamin E, irradiated at 75 kGy in air and aged 4 weeks; (c) Oxidation indexes ofUHMWPE blended with increasing concentrations of vitamin E (0–500 ppm), irradiated at 75 kGy inair and aged 2/4 weeks. Adapted from [133], with permission.

The wear resistance of this 2nd generation highly crosslinked formulation has been extensivelytested in several in vitro experiments, under a variety of challenging conditions, and has been

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compared to conventional and 1st generation highly crosslinked formulations before and after bothaccelerated and shelf-aging.

In a POD wear test, highly crosslinked Vitamin E-doped PE exhibited comparable wear rates to1st generation highly crosslinked PE irradiated to the same dose [136], while it demonstrated a 4-foldto 10-fold decrease, respectively, from that of conventional UHMWPE in a hip simulator experimentwith and without the addition of third-body particles [137].

Bellare et al. [138] compared the wear rates of vitamin E blended (1000 and 5000 ppm) vs.virgin UHMWPE, gamma irradiated to 30 and 100 kGy, before and after shelf aging for two years.The samples were also characterized for physical properties and crosslinking density: it was found thatthe crosslinking density increases with the radiation dose, but decreases with the vitamin E content.This was not surprising, as it is known that vitamin E, as a radical scavenger, can inhibit the crosslinkingreactions [19]. Accordingly, the wear rates of the vitamin E containing samples were comparativelyhigher than that of virgin PE irradiated to the same dose, but lower than that of unirradiated PE.Conversely, after two years of shelf aging, virgin, irradiated, UHMWPE showed high oxidation levels,while vitamin E, as expected, proved to be very effective in retarding oxidation.

Similarly, while comparing the wear behavior of standard, unirradiated PE to that of twoformulations of crosslinked polyethylene, with and without vitamin E (1000 ppm), both irradiatedto 70 kGy, Affatato et al. [139] found that the vitamin E blended PE exhibited a much lower wearthan conventional ultra-high molecular weight polyethylene, but wore more than the traditionalcrosslinked polyethylene. Again, this was correlated to the lower crosslinking density induced by thesame radiation dose in the presence of vitamin E.

These observations suggest that, if vitamin E is necessary to avoid oxidation, then the radiationdose must be optimized in order to obtain enough crosslinking density to preserve the wear resistanceof unstabilized, crosslinked PE.

Given the concerns mentioned above on the use of 1st generation highly crosslinked PE in kneearthroplasty, the vitamin E crosslinked formulations represented an attractive alternative, in particularin this application. For this reason, many experimental studies investigated the performance of vitaminE stabilized PE for use in the knee with promising results. For example, while comparing the wearrate of two designs (cruciate-retaining and posterior-stabilized) of highly crosslinked UHMWPEdoped with vitamin E to that of γ-inert–sterilized direct compression-molded UHMWPE, Haider andcoworkers [140] found that the former exhibited up to 86% reduction in wear for both designs.

In another knee simulator experiment, UHMWPE blended with 1000 ppm of vitamin E andradiation sterilized with 30 ± 2 kGy, was artificially aged according to ASTM F2003-2 and testedfor 5 million cycle without showing structural failures, as conventional PE did under similarconditions [141]. Similarly, vitamin E-stabilized highly crosslinked components tested after acceleratedaging, in comparison to standard, unaged, UHMWPE, demonstrated a 57% reduction in wear [142].

Teramura and coworkers [143] evaluated the wear behavior of direct compression molded tibialcomponents, made of virgin and vitamin E blended (3000 ppm) UHMWPE. The components weregamma sterilized in air (ca. 25 kGy) and aged at 80 ◦C in air for 23 days. It was demonstrated thatthe wear behavior of the vitamin E-containing UHMWPE was not significantly affected by aging andshowed a 12-fold reduction, compared to that of the aged virgin UHMWPE. The wear debris particleswere also evaluated for shape and size and no significant differences were observed between thetwo materials.

5.5. The Effects of Vitamin E on UHMWPE Wear Debris

Bladen et al. [144] demonstrated, as well, that particles generated by UHMWPE in a pin-on-platewear simulator with and without VE were not significantly different in size distribution. They alsoinvestigated the biological activity of particles containing doses of vitamin E up to 30,000 ppm,and found that the vitamin E-containing particles secreted much lower levels of osteolytic mediators,

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tumor necrosis factor-alpha and interleukin, than particles of virgin UHMWPE at comparablevolume doses.

To investigate the effects of particulate debris in vivo, Bichara et al. [145] compared the effectof clinically-relevant sized particulate debris from a crosslinked vitamin E-doped (8000 ppm) vs.a crosslinked/remelted UHMWPE bearing component in a murine calvarial bone model. A statisticallysignificant difference in the amount of fibrous tissue was observed between the two materials,with virgin UHMWPE wear particles inducing the greatest amount of inflammatory tissue.

In addition, it has been shown that vitamin E may also exert some antibacterial activity [146–148].This is likely due to differences in the surface hydrophilicity between virgin and vitamin E-stabilizedpolyethylene that in turn results in slightly different protein adhesion and biofilm formation.

5.6. Clinical Outcomes and Retrieval Studies

Literature reports on the clinical outcome of vitamin E stabilized PE are still quite limited innumber, but their results are overall promising.

One recent study [149] comparing vitamin E-blended crosslinked polyethylene and conventionalgamma-inert sterilized at three years follow up, demonstrated that the femoral head penetrationwas significantly lower for vitamin E-blended HXLPE and similar to that reported for 1st generationHXLPE. Also, no specific complications related to the material were reported in the short-term.

Prospective studies at two to three years follow-up demonstrated no significant differences infemoral head penetration rates between vitamin E doped and virgin highly crosslinked liners [150–152].

However, one study reporting head penetration into vitamin E doped highly crosslinked linersat five years demonstrated less wear compared to that previously reported for 1st generation highlycrosslinked PE, at the same interval of five years. Further, the study demonstrated that, after settling ofthe liners in the early period, no significant head penetration occurred from two- to five-year follow-upand the authors remarked that, overall, the wear observed in the study was well below that at whichosteolysis becomes a serious concern [153].

Rowell et al. [154] analyzed 15 surgically retrieved vitamin E-stabilized crosslinked UHMWPEliners to assess their oxidative stability, extent of lipid absorption in vivo, free radical content,hydroperoxide index and extent of visible wear damage after in vivo service (0.1–36.6 months). Theirresults evidenced promising results, in terms of oxidative resistance and absence of significant surfacedamage, while also suggesting long-term stability through a reduction in free radical content over timeand lack of oxidation after ex vivo aging in air.

Similarly, Currier et al. [155] analyzed 25 antioxidant containing polyethylene tibial insertretrievals, including one formulation with an antioxidant other than vitamin E, with in vivo time of0–3 years. All of the antioxidant materials appeared to be effective at minimizing oxidation over thein vivo period of the study. In addition, the authors speculated that the absence of subsurface peakoxidation suggest that antioxidant PE could be successful in preventing oxidation-mediated fatigue.

6. Conclusions

UHMWPE remains the most commonly used bearing material in total joint arthroplasty due to itslong and relatively successful history. However, UHMWPE is a complex material and its mechanicaland tribological behavior is strongly dependent on the morphology and chemical alterations inducedby processing conditions, such as sterilization using ionizing radiation or crosslinking. The need forincreasing the life expectancy of the implants, in order to meet the demand in younger and activepatients, has led to a considerable evolution in the manufacturing of the UHMWPE orthopedic devicesover the last few decades. From gamma-air sterilized “historical” polyethylenes, to the first and secondgeneration of highly crosslinked materials, the wear resistance, mechanical properties and overallperformances of the UHMWPE biomaterials have greatly improved, as has been extensively reportedin the literature. Advances in the sterilization techniques have enabled a substantial reduction ofthe oxidative degradation experienced by “historical” implants, greatly lowering the incidence of

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wear-induced osteolysis and early mechanical failures. First generation crosslinked PE has furtherreduced wear, but at the expenses of fatigue resistance and/or oxidative stability, while 2nd generationcrosslinked PE has been introduced to overcome the latter drawback and, overall, it has shownpromising, yet early results, despite some issues regarding the oxidative stability of the sequentiallyirradiated and annealed PE.

Nevertheless, the clinical outcome of some of the newest formulations is still largely unexplored.It is therefore of paramount importance to ensure a close, continuous monitoring of the clinicalperformances of the contemporary UHMWPE biomaterials.

Conflicts of Interest: The authors declare no conflict of interest.

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